Our long-term objective is to determine the function of intestinal cytochrome P450 (P450) enzymes in drug metabolism and toxicity. The focus of this proposal is on the characterization of a novel transgenic mouse model for studying the in vivo function of intestinal P450 enzymes in drug/xenobiotic clearance. In preliminary studies, we have generated an intestinal epithelium (IE)-specific NADPH-cytochrome P450 reductase (Cpr) gene knockout mouse model (designated IE-Cpr-null). The gene product of Cpr is the obligatory electron donor to all microsomal P450s. Thus, using the IE-Cpr-null mouse model, we can study the combined roles of IE microsomal P450 enzymes in intestinal xenobiotic metabolism and toxicity. We will use this mouse model to test the central hypothesis that IE P450-mediated drug metabolism can substantially lower the oral bioavailability of numerous drugs/xenobiotics. In Aim 1, we will further characterize the newly generated IE-Cpr-null mouse, in order to identify its full utility. In Aim 2, we will directly determine the role of IE CPR/P450s in the first-pass clearance of oral drugs using the IE-Cpr-null mouse model. In Aim 3, we will test the hypothesis that small intestinal P450-mediated first-pass clearance of ingested dietary or xenobiotic chemicals influences the ability of these chemicals to regulate gene expression in the small intestine and extra-gut organs. Through the proposed studies, we hope to establish the utility of the novel IE-Cpr-null mouse model for identifying those oral drugs/xenobiotics, for which systemic bioavailability (which affects drug efficacy or, alternatively, extent of adverse drug reactions) is substantially influenced by SI P450-mediated first-pass metabolism. PUBLIC HEALTH RELEVANCE: The mutant mouse named IE-Cpr-null will be a powerful tool for determination of the role of intestinal P450 enzymes in limiting the systemic levels of numerous drugs and other foreign chemicals and dietary ingredients. Such knowledge is currently difficult to obtain, and yet is critical for optimizing the effectiveness and safety of numerous clinically important drugs.